U.S. patent application number 10/824731 was filed with the patent office on 2004-10-21 for substituted quinazoline compounds useful as p38 kinase inhibitors.
Invention is credited to Dunn, James Patrick, Goldstein, David Michael, Stahl, Christoph Martin, Trejo-Martin, Teresa Alejandra.
Application Number | 20040209904 10/824731 |
Document ID | / |
Family ID | 33300076 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040209904 |
Kind Code |
A1 |
Dunn, James Patrick ; et
al. |
October 21, 2004 |
Substituted quinazoline compounds useful as P38 kinase
inhibitors
Abstract
Compounds having the formula (I), 1 are useful as p38 kinase
inhibitors, wherein R.sup.4 and R.sup.5 are hydrogen, halogen,
cyano, haloalkyl, or haloalkoxy, but are not both hydrogen; R.sup.6
and R.sup.7 are optional substituents, and Q is a non-aromatic
moiety as defined in the specification.
Inventors: |
Dunn, James Patrick; (Los
Altos, CA) ; Goldstein, David Michael; (San Jose,
CA) ; Stahl, Christoph Martin; (Freiburg, DE)
; Trejo-Martin, Teresa Alejandra; (Union City,
CA) |
Correspondence
Address: |
ROCHE PALO ALTO LLC
PATENT LAW DEPT. M/S A2-250
3431 HILLVIEW AVENUE
PALO ALTO
CA
94304
US
|
Family ID: |
33300076 |
Appl. No.: |
10/824731 |
Filed: |
April 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60463467 |
Apr 16, 2003 |
|
|
|
Current U.S.
Class: |
514/266.2 ;
514/266.4; 544/284; 544/293 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 25/28 20180101; A61P 19/02 20180101; C07D 239/84 20130101;
A61P 19/00 20180101; A61P 9/10 20180101; A61P 31/04 20180101; C07D
405/12 20130101; A61P 9/00 20180101; A61P 1/04 20180101; A61P 11/00
20180101; A61P 29/00 20180101; C07D 401/12 20130101 |
Class at
Publication: |
514/266.2 ;
514/266.4; 544/284; 544/293 |
International
Class: |
A61K 031/517; C07D
43/02 |
Claims
1. A compound having the Formula (I): 32or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: Q is
--C(R.sup.1R.sup.2R.sup.3); R.sup.1 is selected from hydrogen,
alkyl, hydroxyalkyl, and alkoxyalkyl; R.sup.2 and R.sup.3 are
selected: (i) independently from: (a) hydrogen, provided if R.sup.1
is hydrogen, only one of R.sup.2 and R.sup.3 may be selected from
hydrogen; (b) alkyl; (c) alkyl substituted with one, two, or three
of halogen, cyano, --OR.sup.8, --SR.sup.8, --C(.dbd.O)R.sup.8,
--C(O).sub.2R.sup.8, --C(.dbd.O)NR.sup.8R.sup.9,
--S(O).sub.pR.sup.10, --C(O).sub.2NR.sup.8R.s- up.9,
--S(O).sub.2NR.sup.8R.sup.9, and/or --NR.sup.8R.sup.9; (d)
--OR.sup.3, --SR.sup.8, --C(.dbd.O)R.sup.8, --C(O).sub.2R.sup.8,
--C(.dbd.O)NR.sup.8R.sup.9, --S(O).sub.pR.sup.10,
--C(O).sub.2NR.sup.8R.s- up.9, and --S(O).sub.2NR.sup.8R.sup.9, (e)
cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted
heterocyclyl, cycloalkylalkyl, substituted cycloalkylalkyl,
heterocycloalkyl, and substituted heterocycloalkyl; or
alternatively, (ii) R.sup.2 and R.sup.3 are taken together to form
an optionally-substituted cycloalkyl or heterocyclyl ring; R.sup.4
and R.sup.5 are independently selected from hydrogen, halogen,
cyano, haloalkyl, and haloalkoxy, provided R.sup.4 and R.sup.5 are
not both hydrogen; R.sup.6 may be attached to carbon atoms C5, C7,
and/or C8 of the quinazoline ring, and when attached to carbon atom
C5 is lower alkyl and when attached to C7 and/or C8 is
independently selected from alkyl, halogen, cyano, nitro, hydroxy,
alkoxy, haloalkoxy, amino, alkylamino, and alkyl substituted with
one to two of halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy,
amino, and/or alkylamino; R.sup.7is attached to any available
carbon atom of the phenyl ring and at each occurrence is
independently selected from alkyl, substituted alkyl, halogen,
cyano, nitro, hydroxy, alkoxy, haloalkoxy, amino, and alkylamino;
R.sup.8 and R.sup.9 are (i) independently selected from hydrogen,
alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
or (ii) when R.sup.8 and R.sup.9 are attached to the same nitrogen
atom (as in --C(O).sub.2NR.sup.8R.sup.9,
--S(O).sub.2NR.sup.8R.sup.9, and --NR.sup.8R.sup.9), R.sup.8 and
R.sup.9 may be taken together to form an optionally-substituted
heterocyclyl ring; R.sup.10 is alkyl, hydroxyalkyl, alkoxyalkyl,
cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted
heterocyclyl; m is 0, 1, 2 or 3; n is 0, 1 or 2; and p is 1 or
2.
2. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: R.sup.1 is
selected from hydrogen and C.sub.1-4alkyl; R.sup.2 and R.sup.3 are
(i) independently selected from C.sub.1-6alkyl and C.sub.1-6alkyl
substituted with one to two of hydroxy, --O(C.sub.1-4alkyl),
--C(O).sub.2(C.sub.1-4al- kyl), and/or
--S(O).sub.p(C.sub.1-4alkyl); or (ii) R.sup.2 and R.sup.3 taken
together form a C.sub.3-7cycloalkyl or a five to six membered
monocyclic heterocyclic ring, wherein each of said rings is
optionally-substituted with 0 to 1 of R.sup.12 and/or 0 to 1 of
R.sup.14; R.sup.4 and R.sup.5 are both halogen; R.sup.12 and
R.sup.14 are independently selected from C.sub.1-4alkyl, hydroxy,
oxo (.dbd.O), --O(C.sub.1-4alkyl), --C(.dbd.O)H,
--C(.dbd.O)(C.sub.1-4alkyl), --C(O).sub.2H,
--C(O).sub.2(C.sub.1-4alkyl), and --S(O).sub.2(C.sub.1-4al- kyl); m
is 0; and n is 0.
3. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein R.sup.1 is
selected from hydrogen and C.sub.1-4alkyl.
4. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein m and n are both
0.
5. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: R.sup.2 and
R.sup.3 are selected (i) independently from: 1) alkyl substituted
with one or two of halogen, cyano, --OR.sup.8, --SR.sup.8,
--C(.dbd.O)R.sup.8, --C(O).sub.2R.sup.8,
--C(.dbd.O)NR.sup.8R.sup.9, --S(O).sub.pR.sup.10,
--C(O).sub.2NR.sup.8R.sup.9, --S(O).sub.2NR.sup.8R.sup.9, and/or
--NR.sup.8R.sup.9, 2) --S(O).sub.pR.sup.10,
--C(O).sub.2NR.sup.8R.sup.9, or --S(O).sub.2NR.sup.8R.sup.9; and 3)
cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted
heterocyclyl, cycloalkylalkyl, substituted cycloalkylalkyl,
heterocycloalkyl, and substituted heterocycloalkyl; or
alternatively, (ii) R.sup.2 and R.sup.3 are taken together to form
an optionally-substituted cycloalkyl or heterocyclyl ring.
6. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: R.sup.2 and
R.sup.3 are independently selected from hydrogen, C.sub.1-6alkyl,
and hydroxy(C.sub.1-6alkyl).
7. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: R.sup.2 and
R.sup.3 are taken together to form an optionally-substituted
C.sub.3-7cycloalkyl or an optionally-substituted heterocyclic
ring.
8. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: R.sup.2 and
R.sup.3 are (i) independently selected from hydrogen,
C.sub.1-4alkyl, and hydroxy(C.sub.1-4alkyl), provided R.sup.2 and
R.sup.3 are not both hydrogen; or (ii) R.sup.2 and R.sup.3 are
taken together to form cyclohexyl, piperidin-4-yl, or
tetrahydropyran-4-yl, wherein each of said rings formed by R.sup.2
and R.sup.3 taken together is optionally-substituted with up to two
of lower alkyl, --OH, --C(O).sub.2(C.sub.1-4alkyl) and/or
--S(O).sub.2(CH.sub.3).
9. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein R.sup.4 and
R.sup.5 are both halogen.
10. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, having the formula:
33
11. A compound according to claim 1, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, having the formula:
34wherein: X is --O--, --C(.dbd.O)--, --N(R.sup.12a)--, or
--CH(R.sup.12b)--; R.sup.12a is selected from hydrogen,
C.sub.1-4alkyl, --C(.dbd.O)R.sup.15, --C(O).sub.2R.sup.15, and
--S(O).sub.2(C.sub.1-4alkyl); R.sup.12b is selected from hydrogen,
C.sub.1-4alkyl, --OR.sup.15, --C(.dbd.O)R.sup.15,
--C(O).sub.2R.sup.15, and --S(O).sub.2(C.sub.1-4alkyl); R.sup.14 is
selected from C.sub.1-4alkyl, oxo (.dbd.O), --OR.sup.15,
--C(.dbd.O)R.sup.15, --C(O).sub.2R.sup.15, and
--S(O).sub.2(C.sub.1-4alky- l); R.sup.15 at each occurrence is
independently selected from hydrogen and C.sub.1-4alkyl; q is 0 or
1; and r is 0, 1, or 2.
12. A compound according to claim 11, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: R.sup.4 and
R.sup.5 are both fluoro.
13. A compound according to claim 11, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein X is --NR
.sup.12a--, R.sup.12a is --S(O).sub.2(C.sub.1-4alkyl), and q is
1.
14. A compound having the Formula (Ip), 35or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein: Q is
--C(R.sup.1R.sup.2R.sup.3) or an optionally-substituted cycloalkyl
or heterocyclyl; R.sup.1 is selected from hydrogen and alkyl;
R.sup.2 and R.sup.3 are independently selected from --Y--R.sup.8,
--Y--OR.sup.8, --Y--SR.sup.8, --Y--S(O).sub.pR.sup.10,
--Y--C(.dbd.O)R.sup.8, and --Y--C(O).sub.2R.sup.8, wherein Y is
C.sub.1-6alkylene; R.sup.4 and R.sup.5 are both halogen; R.sup.8 is
selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl,
provided R.sup.8 is not arylalkyl or heteroarylalkyl; R.sup.10 is
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocyclyl, or substituted heterocyclyl, provided R.sup.10 is not
arylalkyl or heteroarylalkyl; and p is 1 or 2.
15. A compound according to claim 14, or an isomer, prodrug; or
pharmaceutically-acceptable salt thereof, wherein R.sup.4 and
R.sup.5 are both fluoro.
16. A compound according to claim 14, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein at least one of
R.sup.2 and R.sup.3 is selected from --Y--OR.sup.8,
--Y--S(O).sub.pR.sup.10, --Y--C(.dbd.O)R.sup.8, and
--Y--C(O).sub.2R.sup.8, wherein Y is C.sub.1-4alkylene.
17. A compound according to claim 14, or an isomer, prodrug, or
pharmaceutically-acceptable salt thereof, wherein Q is an
optionally-substituted monocyclic cycloalkyl or heterocyclyl
ring.
18. A method for treating a p38-mediated disorder in a patient
comprising administering to the patient in need of such treatment,
an effective amount of a compound having the formula (II): 36or an
isomer, prodrug, or pharmaceutically-acceptable salt thereof,
wherein: Q.sup.a is selected from alkyl, substituted alkyl,
heteroalkyl, or an optionally-substituted cycloalkyl or
heterocyclic ring, provided that Q is not arylalkyl or
heteroarylalkyl; Y is --O--, --S--, or --NR'--, wherein R' is
hydrogen, lower alkyl, or lower alkyl substituted with OH; R is
alkyl, substituted alkyl, or optionally-substituted aryl,
heteroaryl, cycloalkyl, or heterocyclyl; R.sup.6 is attached to any
available carbon atom of the quinazoline ring and at each
occurrence is independently selected from alkyl, substituted alkyl,
halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, cycloalkyl,
substituted cycloalkyl, heterocyclyl, substituted heterocyclyl,
aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
m is 0, 1, 2 or 3.
19. The method of claim 18, comprising administering to the patient
an effective amount of a compound having the formula (II), or an
isomer, prodrug, or pharmaceutically-acceptable salt thereof,
wherein: Y is --O--; R is C.sub.1-6alkyl or phenyl
optionally-substituted with one to two groups selected halogen,
haloalkyl, and haloalkoxy; Q is selected from (i) C.sub.1-6alkyl,
(ii) C.sub.1-6alkyl substituted with one to two groups selected
from hydroxy, --O(C.sub.1-4alkyl), --S(.dbd.O)(C.sub.1-4alkyl),
--S(O).sub.2(C.sub.1-4alkyl), and/or --C(O).sub.2(C.sub.1-4alkyl);
or (iii) cyclohexyl, piperidinyl, or tetrahydropyranyl, wherein
each of said rings is optionally substituted with one of OH,
--C(O).sub.2(C.sub.1-4alkyl) or --S(O).sub.2(C.sub.1-4alk- yl); and
m is 0.
20. A pharmaceutical composition comprising a therapeutically
effective amount of compound according to claim 1 in combination
with a pharmaceutically-acceptable excipient.
21. A method for treating a p38-mediated disorder in a patient
comprising administering to the patient in need of such treatment,
an effective amount of a compound according to claim 1.
22. The method of claim 21, wherein the p38-mediated disorder is
selected from the group consisting of arthritis, Crohn's disease,
Alzeihmer's disease, adult respiratory distress syndrome, chronic
obstructive pulmonary disease, asthma, stroke, sepsis, myocardial
infarction, and spondylitis.
23. A process for preparing a compound of formula (I) 37wherein Q
is --C(R.sup.1R.sup.2R.sup.3); R.sup.1 is selected from hydrogen,
alkyl, hydroxyalkyl, and alkoxyalkyl; R.sup.2 and R.sup.3 are each
independently hydrogen, provided if R.sup.1 is hydrogen, only one
of R.sup.2 and R.sup.3 may be selected from hydrogen; alkyl; alkyl
substituted with one, two, or three of halogen, cyano, --OR.sup.8,
--SR.sup.8, --C(.dbd.O)R.sup.8, --CO.sub.2R.sup.8,
--C(.dbd.O)NR.sup.8R.sup.9, --S(O).sub.pR.sup.10,
--CO.sub.2NR.sup.8R.sup.9, --SO.sub.2NR.sup.8R.sup.- 9, and/or
--NR.sup.8R.sup.9; --OR.sup.8, --SR.sup.8, --C(.dbd.O)R.sup.8,
--CO.sub.2R.sup.8, --C(.dbd.O)NR.sup.8R.sup.9, --SO.sub.pR.sup.10,
--CO.sub.2NR.sup.8R.sup.9, and --SO.sub.2NR.sup.8R.sup.9;
cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted
heterocyclyl, cycloalkylalkyl, substituted cycloalkylalkyl,
heterocycloalkyl, and substituted heterocycloalkyl; or
alternatively R.sup.2 and R.sup.3 are taken together to form an
optionally-substituted cycloalkyl or heterocyclyl ring; R.sup.4 and
R.sup.5 are independently selected from hydrogen, halogen, cyano,
haloalkyl, and haloalkoxy, provided R.sup.4 and R.sup.5 are not
both hydrogen; R.sup.6 may be attached to carbon atoms C5, C7,
and/or C8 of the quinazoline ring, and when attached to carbon atom
C5 is lower alkyl and when attached to C7 and/or C8 is
independently selected from alkyl, halogen, cyano, nitro, hydroxy,
alkoxy, haloalkoxy, amino, alkylamino, and alkyl substituted with
one to two of halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy,
amino, and/or alkylamino; R.sup.7 is attached to any available
carbon atom of the phenyl ring and at each occurrence is
independently selected from alkyl, substituted alkyl, halogen,
cyano, nitro, hydroxy, alkoxy, haloalkoxy, amino, and alkylamino;
R.sup.8 and R.sup.9 are (i) independently selected from hydrogen,
alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
or (ii) when R.sup.8 and R.sup.9 are attached to the same nitrogen
atom (as in --C(O).sub.2NR.sup.8R.sup.9,
--S(O).sub.2NR.sup.8R.sup.9, and --NR.sup.8R.sup.9), R.sup.8 and
R.sup.9 may be taken together to form an optionally-substituted
heterocyclyl ring; R.sup.10 is alkyl, hydroxyalkyl, alkoxyalkyl,
cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted
heterocyclyl; m is 0, 1, 2 or 3; n is 0, 1 or 2; and p is 1 or 2;
wherein said process comprises: (i) providing a compound of formula
(10) 38wherein X is a leaving group; and (ii) contacting said
compound of formula (10) with a compound of the formula
Q-NH.sub.2.
24. The process of claim 23, wherein said compound of formula (10)
is provided by contacting a compound of formula (9) with t-butyl
nitrite: 39
Description
RELATED APPLICATIONS
[0001] This applications claims priority from U.S. provisional
patent application serial No. 60/463,467, filed Apr. 16, 2003,
incorporated herein by reference in full.
FIELD OF THE INVENTION
[0002] The present invention relates to certain quinazoline
compounds useful as p38 protein kinase inhibitors. In particular,
the present invention relates to 2-amino-6-phenoxy substituted
quinazoline compounds, pharmaceutical preparations comprising the
same, and methods for using them.
BACKGROUND OF THE INVENTION
[0003] Mitogen-activated protein kinases (MAP) are a family of
proline-directed serine/threonine kinases that activate their
substrates by dual phosphorylation. The kinases are activated by a
variety of signals, including nutritional and osmotic stress, UV
light, growth factors, endotoxin, and inflammatory cytokines. One
group of MAP kinases is the p38 kinase group which includes various
isoforms (e.g., p38.alpha., p39.beta., p38.gamma. and p38.delta.).
The p38 kinases are responsible for phosphorylating and activating
transcription factors (as well as other kinases), and are
themselves activated by physical and chemical stress,
pro-inflammatory cytokines, and bacterial lipopolysaccharide.
[0004] More importantly, the products of the p38 phosphorylation
have been shown to mediate the production of inflammatory
cytokines, including TNF, IL-1, IL-6, and cyclooxygenase-2 (COX-2).
Each of these cytokines has been implicated in numerous disease
states and conditions. For example, TNF-.alpha. is a cytokine
produced primarily by activated monocytes and macrophages.
Excessive or unregulated production of TNF-.alpha. has been
implicated as playing a causative role in the pathogenesis of
rheumatoid arthritis. More recently, inhibition of TNF production
has been shown to have broad application in the treatment of
inflammatory conditions, inflammatory bowel disease, Alzheimer's
disease, Crohn's disease, multiple sclerosis, and asthma.
[0005] Additionally, TNF has been implicated in viral infections,
such as HIV, influenza virus, and herpes virus, including herpes
simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2),
cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr
virus, human herpes virus-6 (HHV-6), human herpes virus-7 (HHV-7),
human herpes virus-8 (HHV-8), pseudorabies, and rhinotracheitis,
among others.
[0006] Similarly, IL-1 is produced by activated monocytes and
macrophages and plays a role in many pathophysiological responses
including rheumatoid arthritis, fever and reduction of bone
resorption.
[0007] The inhibition of these cytokines by inhibition of the p38
kinase would be beneficial in controlling, reducing and alleviating
many of these disease states. p38 MAP kinase inhibitors have
demonstrated efficacy in several disease models including arthritis
and other joint diseases, sepsis, stroke, myocardial injury,
respiratory inflammatory diseases such as chronic obstructive
pulmonary disease and asthma, and a wide range of inflammatory
conditions. The present invention provides certain
2-amino-6-phenoxy substituted quinazoline compounds useful in
inhibiting p38 kinase. U.S. patent application Ser. No. ______
(Attorney Docket R0164B-Reg), filed concomitantly herewith and
assigned to the present assignee, discloses 2-amino-6-phenoxy
substituted 7-aza-quinazoline compounds useful as p38 kinase
inhibitors, and the entire contents of said application is hereby
incorporated herein by reference.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to compounds having the
Formula (I): 2
[0009] and isomers, prodrugs, and pharmaceutically-acceptable salts
thereof, wherein:
[0010] Q is --C(R.sup.1R.sup.2R.sup.3);
[0011] R.sup.1 is hydrogen, alkyl, hydroxyalkyl, or
alkoxyalkyl;
[0012] R.sup.2 and R.sup.3 are selected:
[0013] (i) independently from:
[0014] (a) hydrogen, provided that if R.sup.1 is hydrogen, only one
of R.sup.2 and R.sup.3 may be hydrogen;
[0015] (b) alkyl;
[0016] (c) alkyl substituted with one, two, or three of halogen,
cyano, --OR.sup.8, --SR.sup.8, --C(.dbd.O)R.sup.8,
--C(O).sub.2R.sup.8, --C(.dbd.O)NR.sup.8R.sup.9,
--S(O).sub.pR.sup.10, --C(O).sub.2NR.sup.8R.s- up.9,
--S(O).sub.2NR.sup.8R.sup.9, and/or --NR.sup.8R.sup.9;
[0017] (d) --OR.sup.8, --SR.sup.8, --C(.dbd.O)R.sup.8,
--C(O).sub.2R.sup.8, --C(.dbd.O)NR.sup.8R.sup.9,
--S(O).sub.pR.sup.10, --C(O).sub.2NR.sup.8R.sup.9, and
--S(O).sub.2NR.sup.8R.sup.9;
[0018] (e) cycloalkyl, substituted cycloalkyl, heterocyclyl,
substituted heterocyclyl, cycloalkylalkyl, substituted
cycloalkylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl;
[0019] or alternatively,
[0020] (ii) R.sup.2 and R.sup.3are taken together to form an
optionally-substituted cycloalkyl or heterocyclyl ring;
[0021] R.sup.4 and R.sup.5 are each independently hydrogen,
halogen, cyano, haloalkyl, or haloalkoxy, provided R.sup.4 and
R.sup.5 are not both hydrogen;
[0022] R.sup.6 may be attached to carbon atoms C5, C7, and/or C8 of
the quinazoline ring, and when attached to carbon atom C5 is lower
alkyl and when attached to C7 and/or C8 is independently selected
from alkyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy,
amino, alkylamino, and alkyl substituted with one to two of
halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, amino, and/or
alkylamino;
[0023] R.sup.7is attached to any available carbon atom of the
phenyl ring and at each occurrence is independently alkyl,
substituted alkyl, halogen, cyano, alkoxy, and haloalkoxy;
[0024] R.sup.8 and R.sup.9 are (i) each independently hydrogen,
alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl;
or (ii) when R.sup.8 and R.sup.9 are attached to the same nitrogen
atom (as in --C(O).sub.2NR.sup.8R.sup.9,
--S(O).sub.2NR.sup.8R.sup.9, and --NR.sup.8R.sup.9), R.sup.8 and
R.sup.9 may be taken together to form an optionally-substituted
heterocyclyl ring;
[0025] R.sup.10 is alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
substituted cycloalkyl, heterocyclyl, or substituted
heterocyclyl;
[0026] m is 0, 1, 2 or 3;
[0027] n is 0, 1 or 2; and
[0028] p is 1 or 2.
[0029] Also provided are pharmaceutical compositions containing at
least one compound according to Formula (I), or a
pharmaceutically-acceptable salt thereof.
[0030] According to another aspect of the invention, there is
provided a method of treating a p38-mediated disorder in a patient
comprising administering to the patient in need of treatment
thereof, a therapeutically-effective amount of at least one
compound having the Formula (II): 3
[0031] and/or isomers, prodrugs, and/or pharmaceutically-acceptable
salts thereof, wherein:
[0032] Q.sup.a is selected from alkyl, substituted alkyl,
heteroalkyl, or an optionally-substituted cycloalkyl or
heterocyclic ring, provided that Q is not arylalkyl or
heteroarylalkyl;
[0033] Y is --O--, --S--, or --NR'--, wherein R' is hydrogen, lower
alkyl, or lower alkyl substituted with OH;
[0034] R is alkyl, substituted alkyl, or optionally-substituted
aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0035] R.sup.6 may be attached to carbon atoms C5, C7, and/or C8 of
the quinazoline ring, and when attached to C5 is lower alkyl and
when attached to carbon atoms C7 and/or C8 of the quinazoline ring
at each occurrence is independently selected from alkyl,
substituted alkyl, halogen, cyano, nitro, hydroxy, alkoxy,
haloalkoxy, cycloalkyl, substituted cycloalkyl, heterocyclyl,
substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; and
[0036] m is 0, 1, 2 or 3.
DETAILED DESCRIPTION OF THE INVENTION
[0037] Definitions
[0038] The following definitions shall apply in the instant
specification and claims, unless otherwise specifically
indicated.
[0039] As used herein, the term "alkyl" means a linear or branched,
saturated monovalent hydrocarbon moiety of one to eight carbon
atoms (preferably one to six carbon atoms), e.g., methyl, ethyl,
n-propyl, 2-propyl, tert-butyl, pentyl, and the like. "Lower alkyl"
means an alkyl of one to four carbon atoms. When a subscript is
used herein following a carbon atom, the subscript refers to the
number of carbon atoms the named group may contain. Thus, for
example, C.sub.1-4-alkyl means an alkyl of one to four carbon atoms
(i.e., lower alkyl) including methyl, ethyl, propyl, iso-propyl,
butyl, and tert-butyl.
[0040] "Alkylene" means a linear or branched, saturated divalent
hydrocarbon moiety of one to eight (preferably one to six) carbon
atoms, e.g., methylene, ethylene, propylene, and the like. When
reference is made to an alkylene linker group, as in
--Y--S(O).sub.2R, --Y--C(O).sub.2NRR, --Y--S(O).sub.2NRR, and so
forth, wherein Y is alkylene, it should be understood that the
alkylene may be a straight or branched-chain alkylene, and the
referenced substituent may be attached to any carbon atom of the
alkylene straight or branched chain. Thus, for example, the group
--Y--S(O).sub.2R, may include, without limitation,
--CH.sub.2--S(O).sub.2R, --CH.sub.2--CH[S(O).sub.2R]--CH.sub.3,
--CH.sub.2--CH{CH.sub.2CH[S(O).sub.2R]CH.sub.3}CH.sub.3, and so
forth.
[0041] When the term "alkyl" is used as a suffix following another
term, as in "phenylalkyl," or "hydroxyalkyl," this is intended to
refer to an alkyl group, as defined above, being substituted with
one or more (preferably one) substituent selected from the other,
specifically-named group. Thus, "phenylalkyl" includes benzyl,
phenylethyl, 2-phenylbutyl, and so forth. "Hydroxyalkyl" includes
2-hydroxyethyl, 1-(hydroxymethyl)-2-methylpropyl,
3,4-dihydroxybutyl, and so forth. Accordingly, as used herein, the
term "hydroxyalkyl" is used to define a subset of heteroalkyl
groups defined below. In the case of a "substituted
cycloalkylalkyl," this is intended to refer to an alkyl group, as
defined above, being substituted with one to two substituted
cycloalkyl groups, as defined below, and likewise, a "substituted
heterocycloalkylalkyl" refers to an alkyl group, as defined above,
being substituted with one to two substituted heterocyclyl groups,
as defined below.
[0042] The term "substituted alkyl" refers to an alkyl group as
defined above having one, two, three, or four substituents
(preferably one to two), independently selected from the group
consisting of halo, haloalkoxy, trifluoromethyl, cyano, nitro,
--OR.sup.a, --SR.sup.a, --S(O)R.sup.c, --S(O).sub.2R.sup.c,
--C(.dbd.O)R.sup.a, --C(.dbd.O)NR.sup.aR.sup.b,
--C(O).sub.2R.sup.a, --C(O).sub.2NR.sup.aR.su- p.b,
--S(O).sub.2NR.sup.aR.sup.b, --NR.sup.aR.sup.b, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted
cycloalkyl, heterocyclyl, and/or substituted heterocyclyl, wherein
R.sup.a and R.sup.b are independently selected from hydrogen,
C.sub.1-6-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl,
and R.sup.c is selected from C.sub.1-6-alkyl, aryl, heteroaryl,
cycloalkyl, and heterocyclyl, and each of R.sup.a, R.sup.b, and
R.sup.c in turn is optionally substituted with one, two, or three
of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano,
amino, alkylamino, SO.sub.2(alkyl), CO.sub.2H, CO.sub.2(alkyl),
C(.dbd.O)H, and/or C(.dbd.O)alkyl, and/or a C.sub.1-4 alkyl
substituted with one to two of halo, hydroxy, alkoxy, haloalkoxy,
cyano, amino, alkylamino, --SO.sub.2(alkyl), CO.sub.2H,
CO.sub.2(alkyl), C(.dbd.O)H, and/or C(.dbd.O)alkyl.
[0043] "Alkoxy" refers to the group OR', wherein R' is alkyl or
substituted alkyl. A "lower alkoxy" is a group --OR' wherein R' is
C.sub.1-4alkyl.
[0044] "Alkoxycarbonyl"0 refers to the group COOR', wherein R' is
alkyl or substituted alkyl as defined above.
[0045] "Alkylsulfonyl" refers to the group --S(O).sub.2R', wherein
R' is alkyl or substituted alkyl as defined above.
[0046] When the term "oxy" is used as a suffix following another
specifically-named group, as in "aryloxy", "heteroaryloxy," or
"arylalkyloxy", this means that an oxygen atom is present as a
linker to the other, specifically-named group. Thus, for example,
"aryloxy" refers to the group --O--R, wherein R is aryl;
"heteroaryloxy" refers to the group --O--R', wherein R' is
heteroaryl; and "arylalkyloxy" refers to the group --O--R", wherein
R" is arylalkyl such as benzyl. Similarly, a "substituted aryloxy"
means the group --O--R, wherein R is substituted aryl, and a
"substituted heteroaryloxy" means the group --O--R', wherein R' is
substituted heteroaryl.
[0047] "Amino" refers to the group NH.sub.2. Thus, an aminoalkyl
refers to an alkyl group having an amino substituent, e.g.,
--CH.sub.2--NH.sub.2, --CH.sub.2--CH.sub.2--NH.sub.2,
--CH.sub.2--CH(NH.sub.2)--CH.sub.3, and so forth. An alkylamino
refers to monoalkylamino groups having the formula --NHR, as well
as dialkylamino groups having the formula --NRR, wherein each R is
independently alkyl, heterocyclyl, substituted heterocyclyl,
cycloalkyl, substituted cycloalkyl, or an alkyl substituted with
one to two groups selected from halo, haloalkyl, hydroxy, alkoxy,
haloalkoxy, cyano, amino, SO.sub.2(alkyl), CO.sub.2H,
CO.sub.2(alkyl), C(.dbd.O)H, and/or C(.dbd.O)alkyl. Accordingly, an
alkylaminoalkyl refers to an alkyl group substituted by one to two
of --NHR and/or --NRR, wherein each R is as defined immediately
above. A "lower aminoalkyl" refers to a group --NHR' or --NR'R',
wherein each R' is C.sub.1-4alkyl.
[0048] When reference is made herein to a carboxmide group
--CO.sub.2NRR (e.g., as in --C(O).sub.2NR.sup.8R.sup.9), it should
be understood this is intended to refer to the group
--O--C(.dbd.O)--NRR.
[0049] The term "aryl" refers to a monovalent, monocyclic or
bicyclic moiety in which at least one of the rings is an aromatic,
carbocyclic moiety. Thus, the term "aryl" includes phenyl,
1-napthyl, and 2-napthyl. The term "aryl" also includes phenyl
rings having fused thereto a second non-aromatic carbocyclic ring,
or a heteroaryl or heterocyclic ring such as benzothienyl,
benzopyrazolyl, benzopiperadinyl, benzocyclohexyl, and the like,
with the understanding, however, that the point of attachment will
be to the phenyl ring.
[0050] A "substituted aryl" is an aryl group as defined above
having one or more (preferably one, two, or three) substituents
independently selected from the group consisting of halo,
haloalkyl, haloalkoxy, cyano, nitro, --Y--R.sup.p, --Y-aryl,
--Y-heteroaryl, --Y-cycloalkyl, --Y-heterocyclyl, --Y--OR.sup.p,
--Y--NR.sup.pR.sup.q, --Y--C(.dbd.O)R.sup.p,
--Y--C(O).sub.2R.sup.p, --Y--C(.dbd.O)NR.sup.pR.su- p.q,
--Y--C(O).sub.2NR.sup.pR.sup.q, --Y--S(O).sub.0-2R.sup.p,
--Y--NRS(O).sub.2R.sup.q, --Y--S(O).sub.2NR.sup.pR.sup.q, and/or
--Y--NRC(.dbd.O)NR.sup.pR.sup.q, where Y is absent or a
C.sub.1-4-alkylene group, R is hydrogen, lower alkyl, or
hydroxy-C.sub.1-4alkyl, and R.sup.p and R.sup.q are independently
selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, and
heterocyclyl, except when said substituent is
--YS(O).sub.1-2R.sup.p or --Y--NRS(O).sub.2R.sup.p, then R.sup.p in
these instances is not hydrogen. In each instance, each of R.sup.p
and/or R.sup.q in turn is optionally substituted with one to two of
alkyl, halo, cyano, hydroxy, alkoxy, amino, alkylamino, haloalkyl,
haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl,
--SO.sub.2(alkyl), CO.sub.2H, CO.sub.2(alkyl), C(.dbd.O)H, and/or
C(.dbd.O)alkyl. A preferred group of aryl substituents are those
selected from alkyl, haloalkyl, halo, hydroxy, amino, alkylamino,
haloalkoxy and alkoxy. Within this group, especially preferred aryl
substituents are halo, alkyl, and alkoxy. More specifically, the
term "substituted aryl" includes, but is not limited to,
fluorophenyl, difluorophenyl, chlorophenyl, methoxyphenyl, and the
like.
[0051] The term "carbocyclic" means a cyclic moiety in which all
ring atoms are carbon atoms, including saturated, partially
unsaturated, and unsaturated rings.
[0052] The term "cycloalkyl" as used herein refers to saturated or
partially unsaturated, monovalent, monocyclic carbocyclic moieties
of three to seven ring carbon atoms and further includes such rings
having a carbon-carbon bridge of one, two, or three bridgehead
carbon atoms, and/or having a second ring fused thereto, with the
understanding that said second fused ring may be a non-aromatic
carbocyclic or heterocyclic ring in which case the point of
attachment will be to the non-aromatic carbocyclic ring moiety.
Thus, the term "cycloalkyl" includes such rings as cyclopropyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
Additionally, one or two carbon atoms of a cycloalkyl group may
optionally contain a carbonyl oxygen group, e.g., one or two atoms
in the ring may be a moiety of the formula --C(.dbd.O)--.
[0053] A "substituted cycloalkyl" is a cycloalkyl group as defined
above having one, two, or three substituents independently selected
from the group consisting of halo, haloalkyl, haloalkoxy, cyano,
nitro, --Y--R.sup.s, --Y-cycloalkyl, --Y-heterocyclyl,
--Y--OR.sup.s, --Y--NR.sup.sR.sup.t, --Y--C(.dbd.O)R.sup.s,
--Y--C(O).sub.2R.sup.s, --Y--C(.dbd.O)NR.sup.sR.sup.t,
--Y--C(O).sub.2NR.sup.sR.sup.t, --Y--S(O).sub.0-2R.sup.s,
--Y--NRS(O).sub.2R.sup.s, Y--S(O).sub.2NR.sup.sR.sup.t, and/or
--Y--NRC(.dbd.O)NR.sup.sR.sup.t, wherein Y is absent or a
C.sub.1-4alkylene group, R is hydrogen, lower alkyl, or
hydroxyC.sub.1-4alkyl, and R.sup.s and R.sup.t are independently
selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, except
when said substituent is --YS(O).sub.1-2R.sup.s or
--Y--NRS(O).sub.2R.sup.s, then R.sup.s in these instances is not
hydrogen. In each instance, each of R.sup.s and/or R.sup.t in turn
is optionally substituted with one to two of lower alkyl, halo,
cyano, hydroxy, alkoxy, amino, alkylamino, haloalkyl, haloalkoxy,
hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl,
--SO.sub.2(alkyl), CO.sub.2H, CO.sub.2(alkyl), C(.dbd.O)H, and/or
C(.dbd.O)alkyl. Preferred substituents for substituted cycloalkyl
groups include -(alkylene).sub.n-hydroxy, -(alkylene).sub.n-lower
alkoxy, -(alkylene).sub.n-S(O).sub.2(lower alkyl), and
-(alkylene).sub.n-CO.sub.2- (lower alkyl), where n is 0, 1, or
2.
[0054] The term "halo," "halide" or "halogen," when referring to a
substituent means fluoro, chloro, bromo, or iodo (preferably fluoro
or chloro).
[0055] The term "haloalkyl" means alkyl substituted with one or
more same or different halo atoms, e.g., --CH.sub.2Cl, --CF.sub.3,
--CH.sub.2CF.sub.3, --CH.sub.2CCl.sub.3, and the like, and further
includes those alkyl groups such as perfluoroalkyl in which all
alkyl hydrogen atoms are replaced by fluorine atoms.
[0056] The term "haloalkoxy" means a haloalkyl group as defined
above linked through an oxygen atom, e.g., it includes
--O--CH.sub.2Cl, --O--CF.sub.3, --O--CH.sub.2CF.sub.3,
--O--CH.sub.2CCl.sub.3, and the like.
[0057] The term "heteroalkyl" as used herein means an alkyl moiety
defined above, wherein one, two or three hydrogen atoms have been
replaced with a substituent independently selected from the group
consisting of --OR.sup.d, --NR.sup.dR.sup.e, and S(O).sub.nR.sub.d
(where n is an integer from 0 to 2), with the understanding that
the point of attachment of the heteroalkyl moiety is through a
carbon atom, wherein R.sup.d and R.sup.e are selected from
hydrogen, alkyl, substituted alkyl (but not including arylalkyl or
heteroarylalkyl), cycloalkyl, substituted cycloalkyl, heterocyclyl,
and substituted heterocyclyl, except when R.sup.d is attached to
S(O).sub.nR.sup.d and n is 1 or 2, then R.sup.d is not hydrogen.
Additionally, when R.sup.d and R.sup.e are attached to the same
nitrogen atom, they may be taken together to form an
optionally-substituted heterocyclyl or heteroaryl ring.
Representative examples include, but are not limited to,
2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxymethylethyl,
2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl,
2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl,
3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl,
aminosulfonylethyl, methylaminosulfonylmethyl,
methylaminosulfonylethyl, methylaminosulfonylpropyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxymethylethyl,
2,3-dihydroxypropyl, and so forth.
[0058] "Heterocyclyl," "heterocyclyl," or "heterocyclic" refers to
a saturated or partially-unsaturated non-aromatic monocyclic or
bicyclic moiety in which one or two ring atoms are heteroatoms
selected from N, O, or S(O).sub.n (where n is an integer from 0 to
2), the remaining ring atoms being carbon atoms, and additionally,
one or two carbon atoms may optionally contain a carbonyl oxygen
group, e.g., one or two atoms in the ring may be a moiety of the
formula --C(.dbd.O)--. Thus, the term heterocyclyl includes rings
such as tetrahydropyranyl, tetrahydrofuryl, piperidinyl,
piperazinyl, morpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
imidazolinyl, and the like. In the case of a bicyclic heterocyclyl,
one of the two rings may be a non-aromatic carbocyclic with the
point of attachment, however, being to the heterocyclic ring.
[0059] A "substituted heterocyclyl" or "substituted heterocycle"
refers to a heterocyclyl group as defined above having one, two, or
three substituents (preferably one to two substituents) selected
from the group consisting of halo, haloalkyl, haloalkoxy, cyano,
nitro, --Y--R.sup.s, --Y-cycloalkyl, --Y-heterocyclyl,
--Y--OR.sup.s, --Y--NR.sup.sR.sup.t, --Y--C(.dbd.O)R.sup.s,
--Y--C(O).sub.2R.sup.s, --Y--C(.dbd.O)NR.sup.sR.su- p.t,
--Y--C(O).sub.2NR.sup.sR.sup.t, --Y--S(O).sub.0-2R.sup.s,
--Y--NRS(O).sub.2R.sup.s, --Y--S(O).sub.2NR.sup.sR.sup.t, and/or
--Y--NRC(.dbd.O)NR.sup.sR.sup.t, wherein Y, R, R.sup.s and R.sup.t
are as defined above for substituted cycloalkyl groups, such that
R.sup.s and R.sup.t are, in turn, at each instance independently
optionally substituted with one to two further groups as recited
above in the definition for substituted cycloalkyl. Preferred
substituents for substituted heterocyclyl groups include
-(alkylene).sub.n-hydroxy, -(alkylene).sub.n-lower alkoxy,
-(alkylene).sub.n-S(O).sub.2(lower alkyl), and
-(alkylene).sub.n-CO.sub.2(lower alkyl), where n is 0, 1, or 2.
[0060] "Heteroaryl" means a monovalent, monocyclic aromatic moiety
of 5 to 6 ring atoms containing one, two, three, or four ring
heteroatoms, each independently selected from N, O, or S, the
remaining ring atoms being carbon, and it also includes such rings
having a second ring fused thereto of five to six ring atoms,
wherein the second fused ring may be aromatic or nonaromatic and
may be carbocyclic, heterocyclic, or a heteroaryl ring, with the
understanding, however, that in such cases the point of attachment
will be to an aromatic ring containing at least one heteroatom.
Thus, the term heteroaryl includes, but is not limited to, pyridyl,
furyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl,
isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuryl,
isobenzofuryl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl,
benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran, and
benzodiazepin-2-one-5-yl, and derivatives thereof.
[0061] A "substituted heteroaryl" is a heteroaryl ring as defined
above having one, two or three (preferably one or two) substituents
selected from the group consisting of halo, haloalkyl, haloalkoxy,
cyano, nitro, --Y--R.sup.p, --Y-aryl, --Y-heteroaryl,
--Y-cycloalkyl, --Y-heterocyclyl, --Y--OR.sup.p,
--Y--NR.sup.pR.sup.q, --Y--C(.dbd.O)R.sup.p,
--Y--C(O).sub.2R.sup.p, --Y--C(.dbd.O)NR.sup.pR.sup.q,
--Y--C(O).sub.2NR.sup.pR.sup.q, --Y--S(O).sub.0-2R.sup.p,
--Y--NRS(O).sub.2R.sup.q, --Y--S(O).sub.2NR.sup.pR.sup.q, and/or
--Y--NRC(.dbd.O)NR.sup.pR.sup.q, wherein Y, R, R.sup.p and R.sup.q
are as defined above for substituted aryl groups, such that R.sup.p
and R.sup.q are, in turn, at each instance independently optionally
substituted with one to two further substituents as recited above
in the definition for substituted aryl. Preferred substituents for
substituted heteroaryl groups include alkyl, haloalkyl,
heterocyclyl, halo, nitro, cyano, and -(alkylene).sub.n-CO.sub.2R
(where n is 0 or 1 and R is hydrogen or alkyl).
[0062] "Leaving group" has the meaning conventionally associated
with it in synthetic organic chemistry, i.e., an atom or a group
capable of being displaced by a nucleophile and includes halo (such
as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy,
alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy,
tosyloxy, trifluoromethanesulfonylox- y, aryloxy (e.g.,
2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the
like.
[0063] "Optional" or "optionally" means that the subsequently
described event may but need not occur, and it includes instances
where the event occurs and instances in which it does not. For
example, "optionally-substituted cycloalkyl" refers to both
cycloalkyl groups and substituted cycloalkyl groups, as defined
above. When the term "optionally-substituted" precedes a number of
different types of rings in one line or string, e.g., as in
"optionally-substituted cycloalkyl or heterocyclyl", or
"optionally-substituted carbocyclic or heterocyclic ring," or
"optionally-substituted aryl, heteroaryl, cycloalkyl, or
heterocyclyl," it is intended that the term
"optionally-substituted" modifies each of the rings identified in
the line or string.
[0064] When the term "optionally-substituted" is used with respect
to a particularly-named cyclic group, such as
"optionally-substituted cyclohexyl," or "optionally-substituted
piperidinyl," it should be understood that the optional
substituents for such particularly-named rings may be selected from
the group of substituents recited above with respect to which the
genus of which the particularly-named group is a member. Thus, for
example, an "optionally-substituted cyclohexyl" may be an
unsubstituted cyclohexyl or a cyclohexyl group having one, two, or
three substituents selected from those recited above for
substituted cycloalkyl.
[0065] When reference is made herein to the C5, C7, or C8 carbon
atoms of the quinazoline ring, the numbering of the ring atoms is
intended to be as follows: 4
[0066] "Pharmaceutically acceptable excipient" means an excipient
that is useful in preparing a pharmaceutical composition that is
generally safe, non-toxic and neither biologically nor otherwise
undesirable. The term includes excipients that are acceptable for
veterinary use as well as human pharmaceutical use. A
"pharmaceutically acceptable excipient" as used in the
specification and claims includes both one and more than one such
excipient.
[0067] "Pharmaceutically acceptable salt" of a compound means a
salt that is generally safe, non-toxic and neither biologically nor
otherwise undesirable, and which possesses the desired
pharmacological activity of the parent compound. Such salts
include: (1) acid addition salts, formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chloro-benzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1carboxylic acid,
glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic
acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary
butyl-acetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanol-amine, triethanolamine, N-methylglucamine, and the
like.
[0068] The terms "pro-drug" and "prodrug" are used interchangeably
herein and refer to any compound which releases an active parent
drug according to Formula I or II in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of a compound of
Formula I or II are prepared by modifying one or more functional
group(s) present in the compound of Formula I or II in such a way
that the modification(s) may be cleaved in vivo to release the
parent compound. Prodrugs include compounds of Formula I or II
wherein a hydroxy, amino, or sulfhydryl group in a compound of
Formula I or II is bonded to any group that may be cleaved in vivo
to regenerate the free hydroxyl, amino, or sulfhydryl group,
respectively. Examples of prodrugs include, but are not limited to,
esters (e.g., acetate, formate, and benzoate derivatives),
carbamates (e.g., N,N-di-methylaminocarbonyl) or hydroxy functional
groups in compounds of Formula I or II, and the like.
[0069] "Protecting group" refers to an atom or group of atoms that
is attached to a reactive group in a molecule and masks, reduces,
or prevents the reactivity of the group to which it is attached.
Examples of protecting groups can be found in Green and Wuts,
Protective Groups in Organic Chemistry (Wiley, 2.sub.nd ed. 1991),
and Harrison and Harrison et al., Compendium of Synthetic Organic
Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative
amino protecting groups include formyl, acetyl, trifluoroacetyl,
benzyl, benzyloxycarbonyl (CBZ), tert-butoxy-carbonyl (Boc),
trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES),
trityl and substituted trityl groups, allyloxycarbonyl,
9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl
(NVOC), and the like. Representative hydroxy protecting groups
include those where the hydroxy group is either acylated or
alkylated such as with benzyl or lower alkyl and trityl ethers as
well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl
ethers, and allyl ethers.
[0070] "Treating" or "treatment" of a disease includes: (1)
preventing the disease, i.e., causing the clinical symptoms of the
disease not to develop in a mammal that may be exposed to or
pre-disposed to the disease but does not yet experience or display
symptoms of the disease; (2) inhibiting the progression of the
disease, i.e., arresting or reducing the development of the disease
or its symptoms; and (3) relieving the disease, i.e., causing
regression of the disease or its symptoms.
[0071] "A therapeutically effective amount" means the amount of a
compound that, when administered to a mammal for treating a
disease, is sufficient to effect a treatment for the disease. The
"therapeutically effective amount" will vary depending on such
factors as the compound being administered, the type of disease
being treated, the progression or severity of the disease state,
and the age, weight, and general health of the mammal being
treated.
[0072] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers." Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers." Stereoisomers that are not mirror images of one
another are termed "diastereomers," and those that are
non-superimposable mirror images of each other are termed
"enantiomers." When a compound has an asymmetric center, for
example, if a carbon atom is bonded to four different groups, a
pair of enantiomers is possible. An enantiomer can be characterized
by the absolute configuration of its asymmetric center and is
described by the (R) and (S) sequencing rules of Cahn and Prelog,
or by the manner in which the molecule rotates the plane of
polarized light and designated as dextrorotatory or levorotatory
(i.e., as (+) or (-)-isomers respectively). A chiral compound can
exist as either an individual enantiomer or as a mixture thereof. A
mixture containing different enantiomers is called a "racemic
mixture."
[0073] The compounds of this invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)-- or (S)-stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a
particular compound in the specification and claims is intended to
include both individual enantiomers and mixtures (racemic or
otherwise) thereof. The methods for the determination of
stereochemistry and the separation of stereoisomers are well-known
in the art (see March, Advanced Organic Chemistry, Chap. 4, 4th
edition, John Wiley and Sons, New York [1992]).
PREFERRED EMBODIMENTES
[0074] While the definition of this invention is set forth in the
Summary of the Invention, certain compounds of Formula (D) are
preferred.
[0075] Preferred compounds according to the invention are those
having Formula (Ip), 5
[0076] and isomers, prodrugs, and pharmaceutically-acceptable salts
thereof, wherein:
[0077] Q is --C(R.sup.1R.sup.2R.sup.3);
[0078] R.sup.1 is selected from hydrogen, alkyl, hydroxyalkyl, and
alkoxyalkyl;
[0079] R.sup.2 and R.sup.3 are (i) independently selected from
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,
substituted heterocyclyl, and alkyl substituted with one, two or
three of --OR.sup.8, --SR.sup.8, --S(O).sub.pR.sup.10,
--C(O).sub.2R.sup.8, cycloalkyl, substituted cycloalkyl,
heterocyclyl, and/or substituted heterocyclyl; or (ii) R.sup.2 and
R.sup.3 are taken together to form an optionally-substituted
non-aromatic carbocyclic or heterocyclic ring;
[0080] R.sup.4 and R.sup.5 are halogen, cyano, trifluoromethyl, or
trifluoromethoxy;
[0081] R.sup.8 and R.sup.9 are independently selected from
hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted
cycloalkyl, heterocyclyl, and substituted heterocyclyl;
[0082] R.sup.10 is alkyl, cycloalkyl, substituted cycloalkyl,
heterocyclyl, or substituted heterocyclyl; and
[0083] p is 1 or 2.
[0084] More preferred are compounds of Formula (Ip) as immediately
defined above, wherein
[0085] R.sup.1 is selected from hydrogen and C.sub.1-4alkyl;
[0086] R.sup.2 and R.sup.3 are (i) independently selected from
hydrogen, C.sub.1-6alkyl, and C.sub.1-6alkyl substituted with
hydroxy, --O(C.sub.1-4alkyl), or --S(O).sub.2(C.sub.1-4alkyl); or
(ii) R.sup.2 and R.sup.3 taken together form a C.sub.3-7cycloalkyl
or a five to six membered monocyclic heterocyclic ring, wherein
each of said rings is optionally-substituted with up to one of
R.sup.12 and/or up to one of R.sup.14;
[0087] R.sup.4 and R.sup.5 are both halogen; and
[0088] R.sup.12 and R.sup.14 are independently selected from
C.sub.1-4alkyl, hydroxy, oxo (.dbd.O), --O(C.sub.1-4alkyl),
--C(.dbd.O)H, --C(.dbd.O)(C.sub.1-4alkyl), --C(O).sub.2H,
--C(O).sub.2(C.sub.1-4alkyl), and --S(O).sub.2(C.sub.1-4alkyl).
[0089] In compounds of Formulae (I) and (Ip), preferred compounds
are those compounds wherein R.sup.1 is selected from hydrogen and
C.sub.1-4alkyl.
[0090] In compounds of Formula (I) and (Ip), preferred compounds
are those wherein one of R.sup.2 and R.sup.3 is selected from alkyl
substituted with one, two or three of --OR.sup.8, --SR.sup.8,
--C(.dbd.O)R.sup.8, --C(O).sub.2R, --C(.dbd.O)NR.sup.8R.sup.9,
--S(O).sub.pR.sup.10, --C(O).sub.2NR.sup.8R.sup.9,
--S(O).sub.2NR.sup.8R.sup.9, cycloalkyl, substituted cycloalkyl,
heterocyclyl, and/or substituted heterocyclyl (wherein R.sup.8 and
R.sup.9 are independently selected from alkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and
substituted heterocyclyl). A more preferred group of compounds are
those wherein R.sup.2 and R.sup.3 are selected from alkyl,
hydroxyalkyl, alkoxyalkyl,
--(C.sub.1-4alkylene)-S(O).sub.pR.sup.10, and
--(C.sub.1-4alkylene)-C(O).sub.2R.sup.8 (wherein R.sup.8 and
R.sup.10 are lower alkyl). Also preferred are those compounds
wherein R.sup.2 and R.sup.3 are taken together to form an
optionally-substituted C.sub.3-7cycloalkyl or an
optionally-substituted heterocyclic ring. Within this group of
preferred compounds, more preferred are those compounds wherein
R.sup.2 and R.sup.3 are taken together to form
optionally-substituted cyclohexyl, piperidin-4-yl, or
tetrahydropyran-4-yl. Preferably, said cycloalkyl and heterocyclic
groups formed by R.sup.2 and R.sup.3 are unsubstituted or
substituted with OH, --O(C.sub.1-4alkyl),
--C(O).sub.2(C.sub.1-4alkyl) and/or --S(O).sub.2(C.sub.1-4alkyl),
more preferably with one of --C(O).sub.2(Et) or
--S(O).sub.2(CH.sub.3).
[0091] In compounds of Formula (I) and (Ip), preferably R.sup.4 and
R.sup.5 are both halogen. More preferred compounds are those
wherein R.sup.4 and R.sup.5 are both fluoro.
[0092] Still further, combinations of the preferred groups
described herein form other preferred embodiments. In this manner,
a variety of preferred compounds are embodied within the present
invention.
[0093] Another group of preferred compounds are those having the
formula, 6
[0094] wherein Q is --C(R.sup.1R.sup.2R.sup.3); R.sup.1 is selected
from hydrogen, alkyl, hydroxyalkyl, and alkoxyalkyl; and
[0095] R.sup.2 and R.sup.3 are (i) independently selected from
hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,
substituted heterocyclyl, and C.sub.1-6alkyl substituted with one
or two of --OR.sup.8, --SR.sup.8, --S(O).sub.pR.sup.10,
--C(O).sub.2R.sup.8, --NR.sup.8R.sup.9, cycloalkyl, substituted
cycloalkyl, heterocyclyl and/or substituted heterocyclyl; or (ii)
R.sup.2 and R.sup.3 are taken together to form an
optionally-substituted non-aromatic carbocyclic or heterocyclic
ring.
[0096] Another group of preferred compounds are those having the
formula: 7
[0097] wherein:
[0098] R.sup.4 and R.sup.5 are both halogen (more preferably
fluoro);
[0099] X is --O--, --C(.dbd.O)--, --N(R.sup.12a)--, or
--CH(R.sup.12b)--;
[0100] R.sup.12a is selected from hydrogen, C.sub.1-4alkyl,
--C(.dbd.O)R.sup.15, --C(O).sub.2R.sup.15, and
--S(O).sub.2(C.sub.1-4alky- l);
[0101] R.sup.12b is selected from hydrogen, C.sub.1-4alkyl,
--OR.sup.15, --C(.dbd.O)R.sup.15, --C(O).sub.2R.sup.15, and
--S(O).sub.2(C.sub.1-4alky- l);
[0102] R.sup.14 is selected from C.sub.1-4alkyl, hydroxy, oxo
(.dbd.O), --OR.sup.15, --C(.dbd.O)R.sup.15,
--C(O).sub.2R.sup.15,and --S(O).sub.2C.sub.1-4alkyl);
[0103] R.sup.15 is selected from hydrogen and C.sub.1-4alkyl;
[0104] q is 0 or 1; and
[0105] r is 0 or 1.
[0106] Even more preferred are compounds as immediately defined
above, wherein X is --NR.sup.12a--, R.sup.12a is
S(O).sub.2(C.sub.1-4alkyl), q is 1, and r is 0.
Utility
[0107] Compounds of Formulae I and II are useful for the treatment
of any disorder or disease state in a human, or other mammal, which
is exacerbated or caused by excessive or unregulated
proinflammatory cytokines (i.e., TNF, IL-1, etc.), or p38 kinase
activation by such mammal. Compounds of Formulae I and II inhibit
p38 kinase in in vitro assays and inhibit TNF-.alpha. or IL-1B
release in cell based assays.
[0108] In view of their activity as inhibitors of p38kinase, the
compounds of the invention are useful for treating inflammatory
diseases, autoimmune diseases, destructive bone disorders,
proliferative disorders, angiogenic disorders, infectious diseases,
neurodegenerative diseases, and viral diseases. Compounds of the
invention are useful in treating arthritis, including but not
limited to rheumatoid arthritis, spondylitis, gouty arthritis,
osteoarthritis, systemic lupus erythematosus (SLE), juvenile
arthritis, and other arthritic conditions. In addition, compounds
of the present invention are useful in treating pulmonary disorders
or lung inflammation, including adult respiratory distress
syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic
obstructive pulmonary disease. Furthermore, compounds of the
present invention are useful in treating viral and bacterial
infections, including sepsis, septic shock, gram negative sepsis,
malaria, meningitis, cachexia secondary to infection or malignancy,
cachexia secondary to acquired immune deficiency syndrome (AIDS),
AIDS, ARC (AIDS related complex), pneumonia, and herpes virus.
Moreover, compounds of the present invention are useful in the
treatment of bone resorption diseases, such as osteoporosis,
endotoxic shock, toxic shock syndrome, reperfusion injury,
autoimmune disease including graft vs. host reaction and allograft
rejections, cardiovascular diseases including myocardial
infarction, atherosclerosis, thrombosis, congestive heart failure,
cardiac reperfusion injury, renal reperfusion injury, liver disease
and nephritis, and myalgias due to infection.
[0109] The compounds of the present invention are also useful for
the treatment of influenza, diabetes, systemic lupus erthrematosis
(SLE), skin-related conditions such as psoriasis, eczema, burns,
dermatitis, keloid formation, and scar tissue formation. Compounds
of the present invention are also useful in treating
gastrointestinal conditions such as inflammatory bowel disease,
Crohn's disease, gastritis, irritable bowel syndrome, and
ulcerative colitis. The compounds of the present invention can also
be used in treating ophthalmic diseases, such as retinitis,
retinopathies, uveitis, ocular photophobia, and acute injury to the
eye tissue. Compounds of the invention also would be useful for
treatment of cancer and angiogenesis, including neoplasia and
metastasis; ophthalmological conditions such as corneal graft
rejection, ocular neovascularization, retinal neovascularization
including neovascularization following injury or infection,
diabetic retinopathy, retrolental fibroplasia and neovascular
glaucoma; ulcerative diseases such as gastric ulcer; pathological,
but non-malignant conditions such as hemangiomas, including
infantile hemangiomas, angiofibroma of the nasopharynx and
avascular necrosis of bone; diabetic nephropathy and
cardiomyopathy; and disorders of the female reproductive system
such as endometriosis.
[0110] The compounds of the present invention are also useful in
treating central nervous system disorders, such as Alzheimer's
disease, multiple sclerosis, and depression.
[0111] In addition, compounds of the present invention are also
useful for preventing the production of cyclooxygenase-2 and thus
are useful in treating those diseases responsive to inhibition of
COX-2, such as fever, edema, and pain, including headache,
neuromuscular pain, dental pain, arthritic pain and pain caused by
cancer.
[0112] Besides being useful for human treatment, compounds of the
present invention are also useful for veterinary treatment of
animals such as companion, exotic, and farm animals, including
mammals, rodents, and the like. More preferred animals include
horses, dogs, and cats.
[0113] Furthermore, compounds of the present invention can be used
in co-therapies, partially or completely, in place of other
conventional antiinflammatory agents, such as together with
steroids, cyclooxygenase-2 inhibitors, NSAIDs, aspirin, DMARDS,
immunosuppressive agents, 5-lipoxygenase inhibitors, LTB.sub.4
antagonists and LTA.sub.4 hydrolase inhibitors.
[0114] As used herein, the term "TNF mediated disorder" refers to
any and all disorders and disease states in which TNF plays a role,
either by control of TNF itself, or by TNF causing another monokine
to be released, such as but not limited to IL-1, IL-6 or IL-8. A
disease state in which, for instance, IL-1 is a major component,
and whose production or action, is exacerbated or secreted in
response to TNF, would therefore be considered a disorder mediated
by TNF.
[0115] As used herein, the term "p38 mediated disorder" refers to
any and all disorders and disease states in which p38 plays a role,
either by control of p38 itself, or by p38 causing another factor
to be released, such as but not limited to IL-1, IL-6 or IL-8. A
disease state in which, for instance, IL-1 is a major component,
and whose production or action is exacerbated or secreted in
response to p38, would therefore be considered a disorder mediated
by p38.
[0116] As TNF-.beta. has close structural homology with TNF-.alpha.
(also known as cachectin), and since each induces similar biologic
responses and binds to the same cellular receptor, the synthesis of
both TNF-.alpha. and TNF-.beta. are inhibited by the compounds of
the present invention. When reference herein is made generally to
"TNF" inhibition, this is intended to encompass both TNF-.alpha.
and TNF-.beta. inhibition, unless specifically delineated
otherwise.
[0117] Abbreviations
[0118] For ease of reference, the following abbreviations are used
in the general synthetic schemes and Examples below:
[0119] EtOH=ethanol
[0120] MeOH=methanol
[0121] EtOAc=ethyl acetate
[0122] DCE=1,2-dichloroethane
[0123] DCM=dichloromethane
[0124] DMF=dimethylformamide
[0125] NaOH=sodium hydroxide
[0126] NMP=1-methyl-2-pyrrolidinone
[0127] TEA or Et.sub.3N=triethylamine
[0128] TFA=trifluoroacetic acid
[0129] THF=tetrahydrofuran
[0130] Mp=melting point
[0131] MW=molecular weight
[0132] h=hour(s)
[0133] rt.=room temperature
[0134] General Synthetic Schemes
[0135] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art. Preferred methods
include, but are not limited to, the general synthetic procedures
described below. These schemes are merely illustrative. Various
modifications to these schemes can be made and will be apparent to
one skilled in the art.
[0136] The starting materials and reagents used are either
available from commercial suppliers such as Aldrich Chemical Co.
(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Enika
Chemie or Sigma (St. Louis, Mo., USA), Maybridge (Dist: Ryan
Scientific, P.O. Box 6496, Columbia, S.C. 92960), etc.; or they can
be prepared by methods known to those skilled in the art following
procedures set forth in the literature. The starting materials and
the intermediates of the reaction may be isolated and purified if
desired using conventional techniques, including but not limited to
filtration, distillation, crystallization, chromatography, and the
like. Such materials may be characterized using conventional means,
including physical constants and spectral data. In the Schemes, the
variables Q, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
etc., are defined as set forth in the Summary of Invention and
claims. 8
[0137] Methyl 5-chloro-2-nitrobenzoate (1) is reacted with an
appropriately-substituted phenol (2) and base such as potassium
carbonate in a solvent such as NMP to form the corresponding
phenoxy-2-nitro-benzoic acid methyl ester (3). Compound (3) is
hydrolyzed upon treatment with basic solution such as NaOH in
water/MeOH to provide benzoic acid (4). Benzoic acid (4) is treated
with thionyl chloride in solvent such as DMF to provide an
intermediate acid chloride, which upon treatment with NH.sub.4OH in
solvent such as THF provides benzamide (5). The nitro-benzamide (5)
can be hydrogenated in solvent such as EtOH to provide
amino-benzamide (6).
[0138] Amino-benzamide (6) can be cyclized to provide
quinazoline-2,4-dione (7) upon treatment with urea in solvent such
as NMP. Compound (7) can be treated with N,N-diethylaniline and
POCl.sub.3 to give 2,4-dichloroquinazoline (8), which, when treated
with NH.sub.3 in a solvent such as MeOH provides compound (9).
Compound (9) can be reacted with t-butyl nitrite in THF to provide
compound (10) which, when coupled with an appropriate amine
NH.sub.2Q, e.g., in NMP, affords compounds of Formula (I). 9
[0139] Compounds having formula (II) are prepared as shown in
Scheme 2, following the same general methodology as described above
for Scheme 1.
EXAMPLE 1
2-[6-(2,4-Difluoro-phenoxy)-quinazolin-2-ylamino]-2-ethyl-propane-1,3-diol
[0140] 10
1A. 5-(2,4-Difluoro-phenoxy)-2-nitro-benzoic acid methyl ester
[0141] 11
[0142] Methyl 5-chloro-2-nitrobenzoate (73 g, 0.34 mol),
2,4-difluorophenol (51.1 g, 0.39 mol) and potassium carbonate (73
g, 0.53 mol) in NMP (200 mL) were stirred at 160.degree. C. for 2
h. The reaction mixture was cooled to room temperature poured into
water (250 mL) and extracted into EtOAc (2.times.100 mL). The
organic layer was washed several times with water, dried over
sodium sulfate, concentrated in vacuo, and the residue was purified
by flash chromatography eluting with hexane: EtOAc (95:5) to yield
66.8 g of 5-(2,4-difluoro-phenoxy)-2-nitro-- benzoic acid methyl
ester (1A).
1B. 5-(2,4-Difluoro-phenoxy)-2-nitro-benzoic acid
[0143] 12
[0144] To a solution of compound (1A) (66 g, 0.21 mol) in
water/MeOH (180/180 mL) was added NaOH (27 g, 0.68 mol), and the
mixture was heated to reflux for 2 h. After cooling to room
temperature, the reaction was acidified with 10% HCl and extracted
into EtOAc. The organic layer was washed with brine, dried over
sodium sulfate, concentrated in vacuo, and crystallized from ether/
hexane to afford 53 g of 5-(2,4-difluoro-phenoxy- )-2-nitro-benzoic
acid (1B).
1C. 5-(2,4-Difluoro-phenoxy)-2-nitro-benzamide
[0145] 13
[0146] A mixture of compound (1B) (53 g, 0.18 mol), thionyl
chloride (51.3 mL) and DMF (1 mL) was stirred at room temperature
for 18 h, then concentrated in vacuo to dryness. This acid chloride
(60.7 g) was dissolved in THF (400 mL), and NH.sub.4OH (235 mL) was
added. The mixture was then stirred for 18 h and concentrated in
vacuo. The residue was purified by flash chromatography eluting
with hexane:EtOAc (4:1) to afford 27.7 g of
5-(2,4-difluoro-phenoxy)-2-nitro-benzamide (1C).
1D. 2-Amino-5-(2,4-difluoro-phenoxy)-benzamide
[0147] 14
[0148] To compound (1C) (27 g, 0.09 mol) in EtOH was added
palladium on activated carbon (2.7 g), and the mixture was stirred
under hydrogen for 18 h. The suspension was filtered through celite
and the filtrate concentrated and dried in vacuo to yield 23 g of
2-amino-5-(2,4-difluoro-- phenoxy)-benzamide (1D).
1E. 6-(2,4-Difluoro-phenoxy)-1H-quinazoline-2,4-dione
[0149] 15
[0150] Compound (1D) (23 g, 0.09 mol) and urea (25.42 g, 0.41 mol)
in NMP (150 mL) were heated to 170.degree. C. for 18 h. After
cooling to room temperature, the reaction mixture was poured into
water (200 mL) and stirred for 1 h. The precipitate was filtered,
washed with water, and dried to afford 22.7 g of
6-(2,4-difluoro-phenoxy)-1H-quinazoline-2,4-dio- ne (1E).
1F. 2,4-Dichloro-6-(2,4-difluoro-phenoxy)-quinazoline
[0151] 16
[0152] Compound (1E) (22.6 g, 0.08 mol), N,N-diethylaniline (7.2
mL) and POCl.sub.3 (248 mL) were heated at 120.degree. C. for 4 h.
After cooling to room temperature, the excess POCl.sub.3 was
evaporated, and the residue was made basic with 10% NaHCO.sub.3 and
extracted into EtOAc (2.times.100 mL). The combined organic layers
were dried over sodium sulfate and evaporated in vacuo. The crude
product was purified by chromatography (silica gel, hexane: EtOAc,
4:1) giving 21.1 g of
2,4-dichloro-6-(2,4-difluorophenoxy)-quinazoline (1F).
1G. 2-Chloro-6-(2,4-difluoro-phenoxy)-quinazolin-4-ylamine
[0153] 17
[0154] Compound (1F) (21 g, 0.06 mol) was suspended in ammonia (100
mL of 2.0 M solution in MeOH) and the solution formed after 30 min
was stirred at room temperature for 18 h. The precipitate was
filtered, the concentrated filtrate triturated with EtOAc, and the
organic layers were combined to yield 21.5 g of
2-chloro-6-(2,4-difluorophenoxy)-quinazolin-4- -ylamine (1G).
1H. 2-Chloro-6-(2,4-difluoro-phenoxy)-quinazoline
[0155] 18
[0156] Compound (1G) (21 g, 0.07 mol) was dissolved in THF (200 mL)
and the solution added dropwise to a solution of t-butyl nitrite
(16.5 mL, 0.14 mol) in THF (100 mL). The mixture was heated to
reflux for 4 h, and after cooling to room temperature, the reaction
mixture was poured into water and extracted with EtOAc (2.times.100
mL). The combined organic layers were dried over sodium sulfate and
evaporated in vacuo. The crude product was purified by
chromatography (silica gel, hexane: EtOAc, 4:1) giving 9.05 g of
2-chloro-6-(2,4-difluoro-phenoxy)-quinazoline (1H).
1I
2-[6-(2,4-Difluoro-phenoxy)-quinazolin-2-ylamino]-2-ethyl-propane-1,3-d-
iol (Example 1)
[0157] Compound (1G) (250 mg, 0.85 mmol) and
2-amino-2-ethyl-1,3-propanedi- ol (298 mg, 2.5 mmol) in NMP (0.25
mL) were stirred at 120.degree. C. for 4 h. After cooling to room
temperature, the reaction mixture was poured into water and
extracted with EtOAc (2.times.25 mL). The combined organic layers
were dried over sodium sulfate and evaporated in vacuo. The crude
product was purified by chromatography (silica gel,
CH.sub.2Cl.sub.2: MeOH, 95:5) to afford 150 mg of the above-titled
compound (Example 1). Mp=110-112.9.degree. C. MW
(M+H).sup.+=376.
EXAMPLES 2-5
[0158] 19
[0159] Compounds having the Formula I(a) above, wherein R.sup.2 and
R.sup.3 have the values set forth in Tables 1 and 2, were prepared
following the same or similar method as described above for EXAMPLE
1, except the appropriate amine was used in place of
2-amino-2-ethyl-1,3-pro- panediol in Step 1I.
1TABLE 1 Ex. Mp No. R.sup.2 R.sup.3 Compound Name (.degree. C.) MW
2 --CH.sub.3 --CH.sub.3 6-(2,4-Difluoro- 160-162.6 315.32
phenoxy)-quinazolin- 2-yl]-(isopropyl)- amine 3
--CH.sub.2CH.sub.2OH --CH.sub.2CH.sub.2OH 3-[6-(2,4-Difluoro-
112.9-113.6 375.37 phenoxy)-quinazolin- 2-ylamino]-pentane-
1,5-diol
[0160]
2TABLE 2 Ex. Mp No. R.sup.2 R.sup.3 Compound Name (.degree. C.) MW
4 --H 20 3-[6-(2,4-Difluoro- phenoxy)-quinazolin-2-
ylamino]-propane-1,2-diol 161.5-162.7 347.32 5 --H 21
6-(2,4-Difluoro-phenoxy)- quinazolin-2-yl]-(2-
methanesulfonyl-ethyl)- amine 160.1-161.5 379.39
EXAMPLE 6
6-(2,4-Difluoro-phenoxy)-quinazolin-2-yl]-(1-methanesulfonyl-piperidin-4-y-
l)-amine
[0161] 22
[0162] 2-Chloro-6-(2,4-difluoro-phenoxy)-quinazoline (250 mg, 0.85
mmol) (compound 1I, prepared as described in Example 1, steps A-H),
and 1-(methylsulfonyl) piperidin-4-amine (228 mg, 1.25 mmol) in NMP
(0.25 mL) were stirred at 120.degree. C. for 18 h. After cooling to
room temperature, the reaction mixture was poured into water and
extracted with EtOAc (2.times.25 mL). The combined organic layers
were dried over sodium sulfate and evaporated in vacuo. The crude
product was purified by chromatography (silica gel, hexane:EtOAc,
1:1) to afford 105 mg of the above-titled Example 6.
Mp=173.9-177.1.degree. C., MW (M+H).sup.+=435.
EXAMPLES 7-10
[0163] 23
[0164] Compounds having the Formula (Ib) above, wherein X has the
values set forth in Table 3, were prepared following the same or
similar method as described above for Example 6, except the
appropriately-substituted amine was used in place of
1-(methylsulfonyl)piperidin-4-amine.
3TABLE 3 Ex. Mp No. X Compound Name (.degree. C.) MW 7 --O--
[6-(2,4-Difluoro- 179-180.9 357.36 phenoxy)-quinazolin-2-
yl]-(tetrahydro-pyran-4- yl)-amine 8 24 4-[6-(2,4-Difluoro-
phenoxy)-quinazolin-2- ylamino]-cyclohexanol 176.2-176.8 371.39 9
25 4-[6-(2,4-Difluoro- phenoxy)-quinazolin-2-
ylamino]-piperidine-1- carboxylic acid ethyl ester 154.1-155.0
428.44 10 --N(H)-- 6-(2,4-Difluoro-phenoxy)- 163.0- 356.37
quinazolin-2-yl]-piperidin- 165.3 4-yl-amine
EXAMPLE 11
(6-Ethoxy-quinazolin-2-yl)-(2-methanesulfinyl-ethyl)-amine
[0165] 26
[0166] 2-Chloro-6-ethoxy-quinazoline (500 mg, 2.4 mmol) and
2-methylsulfanyl-ethylamine (0.67 mL, 7.25 mmol) in NMP (0.5 mL)
were stirred at 80.degree. C. for 18 h. After cooling to room
temperature, the reaction mixture was poured into water and
extracted with EtOAc (2.times.25 mL). The combined organic layers
were dried over sodium sulfate and evaporated in vacuo. The crude
product was dissolved in DCM (5 mL) and cooled in an ice bath.
3-Chloroperoxybenzoic acid (911 mg, 5.2 mmol) was then added, and
the reaction mixture was stirred for 5 h, diluted with EtOAc (15
mL), washed with 5% NaHCO.sub.3 (10 mL), dried over sodium sulfate,
and evaporated in vacuo. The crude product was purified by
chromatography (silica gel, first EtOAc 100%, then
CH.sub.2Cl.sub.2:MeOH [95:5]) to afford 250 mg of the above titled
Example 11. Mp=152.7-154.6.degree. C., MW (M+H).sup.+=280.
EXAMPLES 12-15
[0167] 27
[0168] Compounds having the Formula II(a) above, wherein Q has the
values set forth in Table 4, were prepared following the same or
similar method as described above for Example 11, except the
appropriate amine was used in place of
2-methylsulfanyl-ethylamine.
4TABLE 4 Ex. Mp No. X Compound Name (.degree. C.) MW 12 28
3-(6-Ethoxy-quinazolin-2- ylamino)-pentane-1,5-diol 291 13 29
(6-Ethoxy-quinazolin-2- yl)-(1-methanesulfonyl-
piperidin-4-yl)-amine 168.0-173 350.44 14 30
4-(6-Ethoxy-quinazolin-2- ylamino)-piperidine-1- carboxylic acid
ethyl ester 164.4-165.0 345 15 31 (6-Ethoxy-quinazolin-2-
yl)-(2-methanesulfonyl- ethyl)-amine 296
EXAMPLE 16
[0169] The following are representative pharmaceutical formulations
containing a compound of (I) or (II).
Tablet Formulation
[0170] The following ingredients are mixed intimately and pressed
into single scored tablets.
5 Ingredient tablet, mg Quantity per compound of this invention 400
cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium
stearate 5
Capsule Formulation
[0171] The following ingredients are mixed intimately and loaded
into a hard-shell gelatin capsule.
6 Ingredient capsule, mg Quantity per compound of this invention
200 lactose, spray-dried 148 magnesium stearate 2
Suspension Formulation
[0172] The following ingredients are mixed to form a suspension for
oral administration.
7 Ingredient Amount compound of this invention 1.0 g fumaric acid
0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben
0.05 g granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg
distilled water q.s. to 100 ml
Injectable Formulation
[0173] The following ingredients are mixed to form an injectable
formulation.
8 Ingredient Amount compound of this invention 0.2 g sodium acetate
buffer solution, 0.4 M 2.0 ml HCl (1N) or NaOH (1N) q.s. to
suitable pH water (distilled, sterile) q.s. to 20 ml
[0174] All of the above ingredients, except water, are combined and
heated to 60-70.degree. C. with stirring. A sufficient quantity of
water at 60.degree. C. is then added with vigorous stirring to
emulsify the ingredients, and water then added q.s. to 100 g.
Suppository Formulation
[0175] A suppository of total weight 2.5 g is prepared by mixing
the compound of the invention with Witepsol.RTM. H-15
(triglycerides of saturated vegetable fatty acid; Riches-Nelson,
Inc., New York), and has the following composition:
9 compound of the invention 500 mg Witepsol .RTM. H-15 balance
EXAMPLE 17
Inhibition of p-38 (MAP) Kinase-In Vitro Assay
[0176] The p-38 MAP kinase inhibitory activity of compounds of this
invention in vitro was determined by measuring the transfer of the
.gamma.-phosphate from .gamma.-.sup.33P-ATP by p-38 kinase to
Myelin Basic Protein (MBP), using the a minor modification of the
method described in Ahn et al., J. of Biol. Chem., Vol. 266 (7),
4220-4227 (1991).
[0177] The phosphorylated form of the recombinant p38 MAP kinase
was expressed with SEK-1 and MEKK in E. Coli (see Khokhlatchev et
al., J. of Biol. Chem. Vol. 272(17), at pp. 11057-11062 (1997)),
and then purified by affinity chromatography using a Nickel
column.
[0178] The phosphorylated p38 MAP kinase was diluted in kinase
buffer (20 mM 3-(N-morpholino)propanesulfonic acid, pH 7.2, 25 mM
.beta.-glycerol phosphate, 5 mM ethylene glycol-bis(beta-aminoethyl
ether)-N,N,N',N'-tetraacetic acid, 1 mM sodium vanadate, 1 mM
dithiothreitol, 40 mM magnesium chloride). Test compound dissolved
in DMSO or only DMSO (control) was added, and the samples were
incubated for 10 min. at 30.degree. C. The kinase reaction was
initiated by the addition of a substrate cocktail containing MBP
and .gamma.-.sup.33P-ATP. After incubating for an additional 20
min. at 30.degree. C., the reaction was terminated by adding 0.75%
phosphoric acid. The phosphorylated MBP was then separated from the
residual .gamma.-.sup.33P-ATP using a phosphocellulose membrane
(Millipore, Bedfrod, Mass.) and quantitated using a scintillation
counter (Packard, Meriden, Conn.).
[0179] The compounds described in the Examples herein were tested
in the above assay and found to have a measurable level of p38
inhibitory activity. As an illustration, Table 5 below lists
approximate p38 inhibitory activities of certain compounds
according to the invention (expressed as IC.sub.50, the
concentration causing 50% inhibition of the p38 enzyme being
analyzed).
10 TABLE 5 Ex. No. IC.sub.50 1 <.10 2 <.03 4 <2 5
.congruent.2 6 <.001 8 <.03 12 >10
[0180] The foregoing discussion of the invention has been presented
for purposes of illustration and description. The foregoing is not
intended to limit the invention to the forms disclosed herein.
Although the description of the invention has included one or more
embodiments and certain variations and modifications, other
variations and modifications are within the scope of the invention,
e.g., as may be within the skill and knowledge of those in the art.
It is intended to obtain rights which include alternative
embodiments to the extent permitted, including alternate,
interchangeable and/or equivalent structures, functions, ranges or
steps to those claimed, whether or not such alternate,
interchangeable and/or equivalent structures, functions, ranges or
steps are disclosed herein, and without intending to publicly
dedicate any patentable subject matter. All publications, patents,
and patent applications cited herein are hereby incorporated by
reference in their entirety.
* * * * *